Therapeutic Drug Monitoring of Thiopurines in Patients With Inflammatory Bowel Disease: Observations From Daily...

Patients with inflammatory bowel disease (IBD) to be treated with thiopurines should undergo preemptive genotyping for reduced-function thiopurine methyltransferase ( TPMT ) polymorphisms. Therapeutic drug monitoring (TDM) is recommended in cases of toxicity or a lack of efficacy. The relationship between TPMT genotype and 6-thioguanine nucleotide (6-TGN) and 6-methylmercaptopurine (6-MMP) concentrations in the early steady state was assessed.

Consecutive adults with IBD to be treated with azathioprine underwent preemptive TPMT genotyping and were dosed accordingly. All patients underwent TDM after 4-6 weeks of treatment and occasionally thereafter.

Of the 235 included patients, 45 were not genotyped for various reasons (45 samples at first TDM, 66 overall). Of the 190 patients who were genotyped, 19 (10%) were heterozygous (*1/*3) (19 samples at first TDM, 32 overall) and 171 (90%) were wild-type (171 samples at first TDM, 280 overall). At first TDM, 7 patients were hypermethylators, and 6 were identified at later TDMs. Compared with patients with a wild-type genotype or those who were not genotyped, those who were heterozygous consistently had markedly higher 6-TGN (2-fold, 3.7-fold if dose-adjusted) and lower 6-MMP (75%-90%, 30%-50% if dose-adjusted) concentrations (pmol/8 × 10 8 red blood cells). Based on the 6-TGN/6-MMP profiles, they were 2-3 times less likely to be classified as receiving "too low of a dose" (6-TGN <235 and 6-MMP <5700 pmol/8 × 10 8 red blood cells), and 4-20 times more likely to be classified as receiving "too high of a dose" (6-TGN >450).

These data support the importance of TPMT genotyping and suggest that thiopurine TDM generates supplementary information and should be performed for all patients.